Elsevier

Seminars in Oncology

Volume 39, Issue 1, February 2012, Pages 47-57
Seminars in Oncology

Molecular pathogenesis of hematologic malignancies
Acute Lymphoblastic Leukemia: Monitoring Minimal Residual Disease as a Therapeutic Principle

https://doi.org/10.1053/j.seminoncol.2011.11.009Get rights and content

Measurement of submicroscopic (minimal) levels of residual disease (MRD) can be used to monitor treatment response much more precisely than morphological screening of bone marrow slides. Several studies have demonstrated that MRD assessment in childhood and adult acute lymphoblastic leukemia (ALL) significantly correlates with clinical outcome. MRD detection is particularly useful for evaluation of early treatment response, but also to monitor disease before and after stem cell transplantation, for early assessment of an impending relapse and in the setting of salvage treatment. Currently, three highly specific and sensitive methodologies for MRD detection are available, namely, real-time quantitative polymerase chain reaction (RQ-PCR) of fusion gene transcripts or breakpoints, RQ-PCR–based detection of clonal immunoglobulin and T-cell receptor (TCR) gene rearrangements, and multiparameter flow cytometric immunophenotyping. Assessment of MRD has gained a prominent position in many ALL treatment studies as a tool for tailoring therapy. Only the results of these studies will answer the question of whether MRD-based treatment intervention is associated with improved outcome.

Section snippets

Analysis of Immunoglobulin and Polymerase Chain Reaction T-Cell Receptor Gene Rearrangements

During early B- and T-cell development, immunoglobulin (Ig) and T-cell receptor (TCR) genes are rearranged by the assembly of variable (V), diversity (D), and joining (J) elements into V(D)J segments encoding the variable regions of both antibodies and TCRs through a process called V(D)J recombination. The resulting junctional regions are specific for the individual cells and its descendants with the level of specificity depending on the number of V, D, and J elements in the germline and the

Prognostic Significance of MRD During Front-line Therapy

The most significant application of MRD for the treatment of de novo ALL is the refinement of initial risk stratification, because several large studies in childhood ALL as well as in adult ALL have shown that the initial MRD kinetics is highly predictive for outcome.5, 6, 12, 22, 25, 26, 27, 36, 37, 46, 65, 68, 81, 82 MRD negativity after induction as measured with a sensitivity of at least 10−4 was shown to be associated with only a 3% (v 39% in the MRD-positive group) relapse rate at 3 years

Methodological Aspects of MRD Assessment Within Clinical Trials

Assessment of MRD has been shown to be feasible even within large multicenter trials. Of the 2,143 patients with B-lineage ALL enrolled on 9900 series treatment protocols of the Children's Oncology Group, in 92% of patients day 29 samples were studied for MRD by flow cytometry at a sensitivity of at least 10−4.24

The AIEOP-BFM ALL 2000 trial used Ig/TCR-based RQ-PCR for MRD assessment in 3,341 patients: 2,365 (71%) patients had two or more sensitive targets (10−4), 671 (20%) patients revealed

MRD as Tool for Treatment Tailoring

There are various ways to use MRD information for tailoring treatment. Most study groups use MRD as tool for risk-group classification during front-line therapy. In childhood ALL, the AIEOP-BFM study group defined three risk groups according to MRD at day 33 and day 78 within their AIOP-BFM ALL 2000 protocol, with randomized treatment de-escalation for MRD–low-risk (LR) patients, treatment intensification for MRD–high-risk (HR) patients, and randomized treatment intensification for

Conclusion

MRD has proven to be an independent prognostic factor in childhood an adult ALL. Quantitative PCR and flow cytometry are currently the most widely used techniques for MRD quantification, each with specific advantages and disadvantages that have to be weighed carefully. In addition, precise MRD levels and optimal sampling time-points have to be defined for each treatment protocol before MRD-based risk stratification can be implemented. Whether or not outcome of patients can be improved by

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    Conflict-of-Interest Disclosure: The authors declare no competing financial interests.

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